Cancer is a serious disease that accounts for a major cause of death. However, therapeutic needs therefor have not yet been met. In recent years, in order to overcome the problem of conventional chemotherapy that causes damage even to normal cells, studies have been intensively conducted regarding cancer therapy using molecularly targeted drugs, in which a drug targeting a specific molecule that is expressed specifically in a cancer cell is designed, and the therapy is then carried out using the drug.
CDH3 is a cell surface antigen that has been identified as a target thereof CDH3 is a membrane protein that has been discovered as a molecule that is calcium-dependently associated with hemophilic cell adhesion (Yoshida and Takeichi, Cell 28: 217-224, 1982). A protein, which has cadherin repeats consisting of approximately 110 amino acid residues having high homology to one another, is referred to as a “cadherin superfamily,” and CDH3 is a main member of the cadherin superfamily.
An increase in the expression of CDH3 in certain types of cancer cells has been reported. Thus, cancer therapy, in which an antibody against cancer cells with higher expression of CDH3 in cancer tissues than in normal tissues is used, has been studied (WO2002/097395 and WO2007/102525).
A large number of antibody drugs have already been placed on the market as molecular-targeted drugs, and a majority of the drugs have antibody-dependent cellular cytotoxicity (ADCC) as a principal mode of action. However, their drug effects are not necessarily sufficient, and thus, technology development is proceeding towards the achievement of a stronger antitumor effect.
An effective means for enhancing the antitumor ability of an antibody is the binding of the antibody to a drug having strong toxicity (toxin). If toxin alone were administered to a patient, it would also affect normal tissues, and thereby, it could not be an effective therapeutic means. However, as a result of the binding of the toxin to an antibody that binds to a tumor cell-specific antigen, the toxin is able to achieve a capacity of killing only tumor cells, while it does not affect normal tissues. Such a drug is referred to as an antibody drug conjugate (ADC). That is to say, a toxin shows no toxicity in a state in which it binds to an antibody. However, when a certain type of antibody binds to a target antigen, it is incorporated into the cell thereof and is then decomposed by a lysosome. Accordingly, the certain type of antibody, to which a toxin binds, is incorporated into the cell, and it is then decomposed therein, so that the toxin is released. As a result, the toxin is expressed only in a specific cell, and the cell is then killed by the effect thereof.
Examples of a drug ingredient used in ADC include bacterial protein toxins such as diphtheria toxin, vegetable protein toxins such as ricin, and low-molecular-weight toxins such as auristatin, maytansinoid or calichemicin and the derivatives thereof.
In ADC, a drug that binds to an antibody circulates in the blood and then accumulates in a target tumor, and thereafter, it exhibits its drug effects. The release of a drug in sites other than tumor sites (the release from the antibody) is not necessarily preferable because it is likely to cause side effects. That is, a drug that binds to an antibody is preferably designed such that it is removed from the antibody after it has been incorporated into a cell. In recent years, from the aforementioned viewpoint, a drug (T-DM1) in which a toxin binds to trastuzumab via a non-cleavable linker (SMCC) has been developed by Genentech. Clinical tests have been carried out on the developed drug, and extremely high clinical effects have been obtained. In addition, an antibody drug conjugate, in which an antibody is bound to a drug ingredient via a cleavable linker, has been developed. For example, the development of an antibody drug conjugate, in which a drug is bound to a HuN901 antibody via a disulfide linker (SPP), that targets cancer expressing NCAM antigen, has been promoted by ImmunoGen.
As described above, the concept of cancer therapy using ADC is known. In the present technical field, there is a demand for other drugs for therapy of various cancers such as lung cancer and colon cancer. An example of a drug that is particularly useful for this purpose is a drug conjugate comprising an anti-CDH3 antibody, which has significantly low toxicity but has advantageous therapeutic effectiveness. These and other restrictions and previous problems can be solved by the present invention.